Continued Challenges in Pancreatic Cancer Research

Tanios Bekaii-Saab, MD: In pancreas cancer, in terms of improving a patient’s outcome, the biggest challenge continues to be that we haven’t really broken the 1-year line of median overall survival for patients. We’ve made a lot of improvements. I think we went from a 3- to 4-month survival to now close to 10, 11 months at the median. We’ve made some significant improvement. So, for some patients, that translated into survival of 3 or 4 years, which is about 3% to 4% of those patients. Whereby in the past, we never had anyone go beyond 2 years. We have some patients who are able to go for much longer with the more modern treatments.

Unfortunately, after a series of a few successes over the last 5 years (I’d say since 2010), in the last year, year-and-a-half, we’ve had a lot of disappointments. A number of combination therapies failed to produce the results we were hoping they would produce. One example is an agent called evofosfamide, which, when combined with gemcitabine, failed to improve outcome versus gemcitabine, although the phase II randomized data look promising.

Another example is found in two studies, JANUS 1 and then JANUS 2, which looked at capecitabine plus ruxolitinib, a janus kinase inhibitor (JAK inhibitor). These did not show an improvement in a prespecified patient population. More recently, we’ve come to learn that two immunotherapy trials were negative. And immunotherapy is all over the place. There is excitement about immunotherapy across multiple malignancies and, obviously, [it] is producing results. In pancreas cancer, it has not translated into such results. So, algenpantucel-L, which is a hyper-acute vaccine, in the adjuvant setting did not show any benefit when added to gemcitabine.

And then CRS-207 and GVAX, another combination of a vaccine and vaccine enhancer which seemed to be very interesting in the phase II randomized study, also came back negative. There has been a series of setbacks, and thus, the challenge continues with this disease in terms of further improvement and drug development.

Philip A. Philip, MD: The development of the prognostic and predictive biomarkers has been very slow in this disease. In fact, we don’t have molecular biomarkers that we have in other cancers like breast cancer or lung cancer, which also have solid tumors we treat. We have been struggling in terms of developing ways to segregate patients; which patients to treat with what drug and then using different drugs in others. At this point in time, I would say that we don’t really have good biomarkers that help us to either predict response or the prognosis of patients that we treat. There are biomarkers that have been developed at this time, but none of them have been tested in a way that I can say for the practicing community of oncologists, “Go and use this biomarker.”

Tanios Bekaii-Saab, MD: The role of the microenvironment in pancreas cancer, and its pathogenesis, is better understood now than it was before, but we still are trying to understand how to target this microenvironment in the clinic. Preclinically, we have a lot of data, meaning in the lab, we understood a lot of the intricacies of that. For example, fibrotic reaction is like a fortress sitting around these pancreas cancer cells, which essentially makes it very difficult for a chemotherapy to penetrate. Also, that microenvironment involves immune cells that are what we call suppressive, meaning they essentially suppress the immune system from attacking the cancer. All the good cells are actually out of that fortress; there’s actually very little blood supply. These tumors are hypovascular, and thus, delivery of good immune cells or chemotherapy is very challenging.

What we’re trying to figure out are ways to actually break down the barrier, and a number of strategies in the past have attempted to modify some of the barriers. More recent developments suggest that for breaking down hyaluronan, which essentially is like the glue that keeps this fortress solid, an agent called PEGPH20 seems to be mostly active when this protein is expressed at high levels. It has shown some promise and is moving into the phase III. We’re understanding a little bit more about the microenvironment. The problem, again, is, how do you just break down that microenvironment so that your immune therapy may become more effective, your chemotherapy may become more effective, other strategies, as well, may become more effective? As long as we haven’t figured out how to break these barriers, it’s going to be very difficult to want to attack the cancer and to modulate the microenvironment.

Transcript Edited for Clarity

Transcript:

Tanios Bekaii-Saab, MD: In pancreas cancer, in terms of improving a patient’s outcome, the biggest challenge continues to be that we haven’t really broken the 1-year line of median overall survival for patients. We’ve made a lot of improvements. I think we went from a 3- to 4-month survival to now close to 10, 11 months at the median. We’ve made some significant improvement. So, for some patients, that translated into survival of 3 or 4 years, which is about 3% to 4% of those patients. Whereby in the past, we never had anyone go beyond 2 years. We have some patients who are able to go for much longer with the more modern treatments.

Unfortunately, after a series of a few successes over the last 5 years (I’d say since 2010), in the last year, year-and-a-half, we’ve had a lot of disappointments. A number of combination therapies failed to produce the results we were hoping they would produce. One example is an agent called evofosfamide, which, when combined with gemcitabine, failed to improve outcome versus gemcitabine, although the phase II randomized data look promising.

Another example is found in two studies, JANUS 1 and then JANUS 2, which looked at capecitabine plus ruxolitinib, a janus kinase inhibitor (JAK inhibitor). These did not show an improvement in a prespecified patient population. More recently, we’ve come to learn that two immunotherapy trials were negative. And immunotherapy is all over the place. There is excitement about immunotherapy across multiple malignancies and, obviously, [it] is producing results. In pancreas cancer, it has not translated into such results. So, algenpantucel-L, which is a hyper-acute vaccine, in the adjuvant setting did not show any benefit when added to gemcitabine.

And then CRS-207 and GVAX, another combination of a vaccine and vaccine enhancer which seemed to be very interesting in the phase II randomized study, also came back negative. There has been a series of setbacks, and thus, the challenge continues with this disease in terms of further improvement and drug development.

Philip A. Philip, MD: The development of the prognostic and predictive biomarkers has been very slow in this disease. In fact, we don’t have molecular biomarkers that we have in other cancers like breast cancer or lung cancer, which also have solid tumors we treat. We have been struggling in terms of developing ways to segregate patients; which patients to treat with what drug and then using different drugs in others. At this point in time, I would say that we don’t really have good biomarkers that help us to either predict response or the prognosis of patients that we treat. There are biomarkers that have been developed at this time, but none of them have been tested in a way that I can say for the practicing community of oncologists, “Go and use this biomarker.”

Tanios Bekaii-Saab, MD: The role of the microenvironment in pancreas cancer, and its pathogenesis, is better understood now than it was before, but we still are trying to understand how to target this microenvironment in the clinic. Preclinically, we have a lot of data, meaning in the lab, we understood a lot of the intricacies of that. For example, fibrotic reaction is like a fortress sitting around these pancreas cancer cells, which essentially makes it very difficult for a chemotherapy to penetrate. Also, that microenvironment involves immune cells that are what we call suppressive, meaning they essentially suppress the immune system from attacking the cancer. All the good cells are actually out of that fortress; there’s actually very little blood supply. These tumors are hypovascular, and thus, delivery of good immune cells or chemotherapy is very challenging.

What we’re trying to figure out are ways to actually break down the barrier, and a number of strategies in the past have attempted to modify some of the barriers. More recent developments suggest that for breaking down hyaluronan, which essentially is like the glue that keeps this fortress solid, an agent called PEGPH20 seems to be mostly active when this protein is expressed at high levels. It has shown some promise and is moving into the phase III. We’re understanding a little bit more about the microenvironment. The problem, again, is, how do you just break down that microenvironment so that your immune therapy may become more effective, your chemotherapy may become more effective, other strategies, as well, may become more effective? As long as we haven’t figured out how to break these barriers, it’s going to be very difficult to want to attack the cancer and to modulate the microenvironment.